Progress in understanding the LDL receptor and HMG-CoA reductase, two membrane proteins that regulate the plasma cholesterol.

The discovery of the low density lipoprotein (LDL) receptor 11 years ago and the subsequent elucidation of its mode of action in the cell and in the body have provided a conceptual framework for understanding the mechan: ns that control the concentration of the most a b u n-h t cholesterol-carrying lipoprotein in human blood. Study of the LDL receptor has taught us that human and animal cells possess at least two mechanisms for obtaining the cholesterol required for synthesis of membranes, steroid hormones, and bile acids: I) they can synthesize cholesterol de novo through the classic cholesterol synthetic pathway, of which the ratedeter-mining step is the reaction catalyzed by 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoA re-ductase); or 2) they can supply themselves with cholesterol through the receptor-mediated endocytosis of LDL, an event that is mediated by the LDL receptor (reviewed in ref. 1). Under the usual circumstances of tissue culture, most cells, such as human skin fibroblasts, rely primarily on LDL receptors as a source of cholesterol. They maintain a low rate of cholesterol synthesis by expressing a small amount of HMG-CoA reductase activity. Cells from individuals with genetic defects in the LDL receptor, such as those with homozygous familial hypercholesterolemia (FH), cannot obtain cholesterol from LDL, and thus they must express increased amounts of HMG-CoA reductase to supply their cholesterol needs (1). In tissue culture cells, the LDL receptor and HMG-CoA reductase are both subject to end-product feedback regulation by cholesterol. When cellular cholesterol levels rise, the synthesis of HMG-CoA reductase and the synthesis of LDL receptors are suppressed. On the other hand, when cells have an increased demand for cholesterol , the production of LDL receptors and HMG-CoA reductase increase (1). A similar type of feedback regulation of these two proteins has been observed in the livers of several animal species. Under certain conditions, the level of LDL in plasma is dictated by the balance between the activities of HMG-CoA reductase and LDL receptors in the liver. If this balance is not preserved, hypercholesterolemia and atherosclerosis can result. If plasma LDL levels are to be kept low, the activities of the LDL receptor and HMG-CoA reductase must be regulated in a coordinate manner in the body as well as in tissue culture. Until quite recently, little was known about the mechanism of regulation of either protein. For this reason, we turned our attention several years ago to studies …